Administering neurokinin receptor antagonists, including the compounds of Formula I and Ia, present various problems with regard to injection site tolerance (e.g., irritability of subject, irritation, inflammation, swelling, and/or redness of the site). Although there have been numerous studies with regard to improving injection site tolerance through the use of various substances, none of these studies, however, have focused on neurokinin receptor antagonist administration.
The compounds of Formula I or Ia are the subject of U.S. Pat. Nos. 5,807,867, 6,222,038 and 6,255,320. The preparation of compounds of Formula I and Ia are described therein. The compound of Ia may also be prepared as described in the co-pending U.S. provisional application No. 60/541,323, commonly owned and assigned to Pfizer, Inc. U.S. Pat. No. 5,393,762 also describes pharmaceutical compositions and treatment of emesis using NK-1 receptor antagonists. Co-pending U.S. provisional application No. 60/540,697, commonly owned and assigned to Pfizer, Inc., describes a method of improving anesthesia recovery in patients by administering the compound of Formula I or Ia. The text of the aforementioned applications, patents and all other references cited in this specification are hereby incorporated by reference in their entirety.
The compound of Formula Ia is a basic drug with two amine functional groups, a secondary amine with a pKa of 4.43 and a tertiary amine with a pKa of 9.31. The citrate salt of the compound of Formula Ia has a solubility of 2.7 mg/mL at a pH of 4.2 in 0.02 M phosphate/0.02 M acetate buffered solution. The desired 10 mgA/mL solubility could be obtained by the addition of salts (e.g. NaCl, CaCl2 or sodium acetate), using a partially-aqueous, oleaginous, or micellar vehicle, or adding a modified, parenterally acceptable cyclodextrin. Generally, however, it was observed that formulations containing cyclodextrins provided improved injection site toleration over other approaches to increasing solubility.
Assuring adequate solubility of a pharmaceutical drug in parenteral formulations is crucial, especially when the drug has low aqueous solubility. pH modification of the solution, drug salt form selection, and the use of co-solvents are common approaches used to achieve adequate solubility. A typical approaches involve excipients, such as complexation agents.
Cyclodextrin may enhance solubility by forming an inclusion complex with the drug molecule whereby the insoluble/hydrophobic drug is inserted into the hydrophobic cavity of the cyclodextrin. The outer hydrophilic shell of the cyclodextrin molecule then enhances solubility of the entire complex. Standard terminology for cyclodextrin complexation identifies the cyclodextrin as a “host” molecule and the drug as a “guest” molecule. Unfortunately, the cyclodextrin used to form the inclusion complex may also bind preservatives, inactivating many poorly water-soluble preservatives.
Sulfobutylether-βcyclodextrin (hereinafter “SBE-CD”) was found to be effective at both increasing the solubility of compound of Formula Ia and ameliorating injection site reactions. Unfortunately, investigation determined that SBE-CD formed complexes with both antimicrobial preservative (e.g. meta-cresol) and the compound of Formula Ia, resulting in competitive binding interactions and, in general, antimicrobial ineffectiveness.
Consequently, it was necessary to obtain an optimal balance between a sufficient concentration of cyclodextrin (e.g., SBE-CD) and antimicrobial preservative (e.g. meta-cresol). While a lower concentration of SBE-CD would increase antimicrobial preservative efficacy, this advantage would be offset, however, by a decrease in acceptable injection site toleration (“IST”). These competing performance characteristics necessitated balancing antimicrobial preservative efficacy (criteria A) and acceptable injection-site-toleration for the product.
Co-pending U.S. provisional application No. 60/540,644, contemporaneously filed with the present application and assigned to and owned by Pfizer Inc., describes a method of improving injection site toleration during the parenteral administration of a composition containing the compound of Formula I and cyclodextrin. A cyclodextrin-compatible preservative was also identified, providing desirable multi-use dosing options. Preferably, meta-cresol is used in the formulation to prevent bacterial and fungal development in the formulation during the proposed extended in-use period.